Shinmura Kazuya, Kato Hisami, Kawanishi Yuichi, Igarashi Hisaki, Inoue Yusuke, Yoshimura Katsuhiro, Nakamura Satoki, Fujita Hidehiko, Funai Kazuhito, Tanahashi Masayuki, Niwa Hiroshi, Ogawa Hiroshi, Sugimura Haruhiko
Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Advanced Research Facilities and Services, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Mol Carcinog. 2017 Aug;56(8):1984-1991. doi: 10.1002/mc.22647. Epub 2017 Mar 30.
Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.0432, Wilcoxon matched pairs test). An immunohistochemical analysis for LAC (n = 237) showed that WDR62 proteins were also significantly overexpressed in LAC (P < 0.0001, Mann-Whitney U test). A Kaplan-Meier analysis demonstrated that patients with LAC who exhibit WDR62 overexpression have a short overall survival (P = 0.0378, log-rank test), and a multivariate analysis revealed that WDR62 overexpression was an independent predictor of a poor survival outcome among LAC patients (hazard ratio, 2.032; 95% confidence interval, 1.071-3.777; P = 0.0305). Next, we examined the functional effect of WDR62 overexpression on the lung cancer cell line H1299. WDR62-overexpressing lung cancer cells exhibited an increase in cell growth. Moreover, the concurrent overexpression of WDR62 and TPX2, a WDR62-interacting protein that is also overexpressed in LAC, induced centrosome amplification in the lung cells. Finally, we disclosed that the concurrent overexpression of WDR62 and TPX2 is common in diverse human cancers, using data from the Cancer Genome Atlas. These results suggested that WDR62 overexpression is associated with a poor prognosis in patients with LAC and leads to an increase in the malignant potential of lung cells.
人WDR62定位于包括中心体在内的细胞质中,已知其与原发性小头畸形有关;然而,WDR62异常在癌症中的作用仍 largely unknown。在本研究中,我们旨在揭示WDR62异常在肺腺癌(LAC)中的病理作用。我们首先使用QRT-PCR分析检测了LAC(n = 64)的WDR62 mRNA表达水平,发现WDR62 mRNA转录本在LAC中显著过表达(P = 0.0432,Wilcoxon配对检验)。对LAC(n = 237)的免疫组织化学分析表明,WDR62蛋白在LAC中也显著过表达(P < 0.0001,Mann-Whitney U检验)。Kaplan-Meier分析表明,WDR62过表达的LAC患者总生存期较短(P = 0.0378,对数秩检验),多变量分析显示WDR62过表达是LAC患者生存结果不良的独立预测因素(风险比,2.032;95%置信区间,1.071 - 3.777;P = 0.0305)。接下来,我们检测了WDR62过表达对肺癌细胞系H1299的功能影响。过表达WDR62的肺癌细胞表现出细胞生长增加。此外,WDR62与TPX2(一种在LAC中也过表达的与WDR62相互作用的蛋白)同时过表达会诱导肺细胞中心体扩增。最后,我们利用癌症基因组图谱的数据揭示,WDR62和TPX2同时过表达在多种人类癌症中很常见。这些结果表明,WDR62过表达与LAC患者的不良预后相关,并导致肺细胞恶性潜能增加。